CD73 Immune Checkpoint Molecule for Drug Development
Overview of CD73
The membrane-bound NT5E (CD73) is an ecto-5'-nucleotidase that hydrolyzes extracellular adenosine monophosphate (AMP) into adenosine and inorganic phosphate. In light of its immune suppressive function and its expression by various tumor entities, CD73 has been considered as a target checkpoint molecule for novel tumor immunotherapy approaches.
CD73 can act as a receptor molecule shown to mediate cell-cell adhesion between lymphocytes and endothelial cells. Moreover, it is demonstrated that CD73 can also interact with extracellular matrix components (ECM). Clinically, in tumor tissues of several cancer types such as colorectal cancer (CRC), breast, and ovarian, high levels of CD73 are associated with low survival rates, which highlight the critical role of CD73 in tumor progression.
CD73 in Endothelial Cell
Studies show that CD73 may contribute to tumor angiogenesis. Restricted tumor T cell infiltration and enhanced tumor growth are related to the high expression of CD73 by a subpopulation of endothelial cells that may contribute to angiogenesis in the tumor microenvironment. In some mouse tumor models, treatment with anti-CD73 monoclonal antibodies (mAb) leads to impaired angiogenesis and decreased tumor growth. Another study shows that the in vitro formation of capillary-like tubes by human umbilical vein endothelial cells is affected by CD73 expression but is independent of its associated enzyme activity.
CD73 in T Cells
Regulatory T cells mediate immunotolerance and help tumor cells evade immunosurveillance by suppressing the immune response. One of the main mechanisms of Treg-mediated tumor immunosuppression depends on the extracellular adenosine produced by CD73. CD73 is highly expressed by Tregs and is frequently coexpressed with CD39. The combination of CD73 and CD39 renders an enzymatically driven accumulation of immunosuppressive adenosine by Tregs. Therefore, the inhibitory function of Tregs derived from CD73 or CD39 is impaired.
Unlike wild-type mouse Treg, CD73/Treg cannot promote tumor growth. Elevated CD73 levels are related to the increase of adenosine generation and the function of immunosuppressive Th17, and increased tumor growth in mouse tumor models. In contrast, genetic ablation of CD73 or treating with interleukin 1 beta (IL-1β) rather than transforming growth factor-beta (TGF-β) to program Th17 cells ex vivo induces stemness. It improves the antitumor effects of adoptive Th17 cell therapy.
CD73 and Immunotherapy
More and more pieces of evidence support the therapeutic potential of targeting the CD73-A2AR axis in numerous types of cancer. A study showed that CD73 mAb treatment inhibited the growth and metastasis of breast tumors. Although single-agent CD73 blockers cannot be cured, CD73 inhibition can increase the antitumor activity of immune checkpoint treatments, including CTLA-4 blockade and PD-1 blockade.
Services at Creative Biolabs
The combination of anti-CD73 and immune checkpoint blockade has shown promising clinical activity in patients with advanced solid tumors. Creative Biolabs offers a wide range of drug development services targeting immune checkpoint CD73.